Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction

Abstract

Intravenous injection of liposomes can cause significant pulmonary hypertension in pigs, a vasoconstrictive response that provides a sensitive model for the cardiopulmonary distress in humans caused by some liposomal drugs. The reaction was recently shown to be a manifestation of "complement activation-related pseudoallergy" (CARPA; Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bünger R, and Alving CR. Circulation 99: 2302-2309, 1999). In the present study we demonstrate that the composition, size, and administration method of liposomes have significant influence on pulmonary vasoactivity, which varied between instantaneously lethal (following bolus injection of 5 mg lipid) to nondetectable (despite infusion of a 2,000-fold higher dose). Experimental conditions augmenting the pulmonary hypertensive response included the presence of dimyristoyl phosphatidylglycerol, 71 mol% cholesterol, distearoyl phosphatidylcholine, and hemoglobin in liposomes, increased vesicle size and polydispersity, and bolus injection vs. slow infusion. The vasoactivity of large multilamellar liposomes was reproduced with human C3a, C5a, and xenoreactive immunoglobulins, and it correlated with the complement activating and natural antibody binding potential of vesicles. Unilamellar, monodisperse liposomes with 0.19 +/- 0.10 microm mean diameter had no significant vasoactivity. These data indicate that liposome-induced pulmonary hypertension in pigs is multifactorial, it is due to natural antibody-triggered classic pathway complement activation and it can be prevented by appropriate tailoring of the structure and administration method of vesicles.

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

“…Although the lipid composition used was the same, the mean hydrodynamic diameter of the vesicles (1200 nm) was greater than that used in this study (400 nm). In theory, the binding of antibodies to liposomes and subsequent activation of the complement system should be proportional to the total vesicular surface area exposed to plasma (Szebeni et al 2000). Comparing the results of Costa Val (2004) and ours, it is likely that the smaller surface area of contact in micrometric vesicles and the lowest dose of lipid applied provided a less effective activation of the complement system.…”

“…There is also the possibility of activating the complement cascade by the alternative route (Funato et al 1992). Probably, the increase of the pulmonary arterial pressure, the reduction of the cardiac debit (Szebeni et al 2000) and the increase of pulmonary and peripheral vascular resistance, generated by the products of the complement, provided a transitional circulatory collapse that resulted in tissue hypoxia. Consequently the sympathetic nervous system was stimulated and resulted in some the clinical signs observed: tachycardia, tachypnea, mydriasis and xerostomia.…”

“…In CARPA, the toxicity reaches a peak between one and five minutes after the administration of the formulation (Szebeni 2005) and, in the present study, the side effects have always been included in the first fifteen minutes after treatment. Indeed, the presence of DCP in the lipid composition of liposomes is probably critical, since it ensures anionic character of the vesicles, which is expected to accelerate protein binding onto the surface of the vesicles (Szebeni et al 2000).…”

“…Since the speed of entry of liposomes in the vascular system is considered critical factor for activation of the complement (Szebeni et al 2000), the intravenous administration of this formulation by continuous infusion in fluid therapy should reduce or eliminate some or all of the side effects observed, without changing the characteristics of the product. Another proposal for reducing the frequency of CARPA would be the premedication of patients with antihistamines and corticosteroids.…”

“…It was also established that vesicle structural factors of liposomes (e.g. phospholipid composition, vesicle size and surface charge) could modulate complement activation and CARPA (Szebeni et al 2000, Szebeni et al 2012.…”